Neuroprotective Effects of Sorghum Polyphenol in Alzheimer’s Disease: In Vitro and In Silico Analyses

Background/Objective: Accumulation of amyloid-beta (Aβ) senile plaques in the human brain is a major hallmark of Alzheimer’s disease (AD), which manifests as progressive decline in memory and cognitive functions and currently lacks effective disease-modifying therapies. Emerging evidence demonstrates that polyphenol-rich plant foods are potential complementary therapies for AD. Methods: In this study, we investigated crude polyphenol extracts (CPEs) and purified polyphenol extracts (PPEs) from three sorghum genotypes for their ability to inhibit Aβ42-induced toxicity in MC-65 cells. Thioflavin T fluorescence, cell viability, mitochondrial function, oxidative stress assays, and Western blotting, along with RNA sequencing and computational analyses, were used to characterise both functional and transcriptomic responses of the cells to polyphenol treatments. Results: CPEs and PPEs inhibited Aβ42 aggregation by 67–76% and significantly reduced Aβ oligomer species. The extracts increased cell viability against Aβ-induced toxicity by more than 70%, decreased intracellular oxidative stress, and enhanced mitochondrial activity by over 80%. Transcriptomic profiling revealed differential modulation of genes associated with ferroptosis and MAPK/NF- κB signalling pathways, indicating regulation of inflammatory and oxidative-stress responses are mechanisms underlying the observed neuroprotection. Conclusions: This study demonstrates that polyphenol extracts from black and red sorghum genotypes exert strong multitarget neuroprotection against Aβ42 toxicity in MC-65 cells. These findings support further evaluation of sorghum-derived polyphenols as complementary therapeutic candidates for AD, with in vivo studies required to establish efficacy and translational potential.